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As RNAi Efforts Advance, Merck Aims to Move siRNA Drug into the Clinic in 'One to Two Years'

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By Doug Macron

While Merck has maintained a low profile regarding its RNAi activities since shelling out $1.1 billion to buy Sirna Therapeutics in early 2007, it continues to work in earnest on the gene-silencing technology and could begin testing an siRNA-based drug in humans as early as 2013, a company official said this week.

“Our strategy is to really ensure that we don't get into the clinic until we've de-risked [a technology] in the preclinical space to the extent that only we can as a full-fledged pharmaceutical company,” Jeremy Caldwell, vice president of RNA therapeutics at Merck, told Gene Silencing News. “It may seem quiet on the outside, but it is actually quite intense on the inside.

“We've made a lot of progress developing RNA therapeutics internally ... and hope to be in the clinic [with an RNAi drug] in the next one to two years,” he said.

The timeline reflects Merck's cautious attitude to bringing an entirely new class of therapeutics to the clinic, one that the company has maintained since the beginning of its involvement in RNAi when it forged a now-terminated alliance with Alnylam Pharmaceuticals in 2003 (GSN 9/12/2003).

Indeed, Merck has never publicly provided guidance on the timing of any of its RNAi drug programs. Even when the company announced plans to acquire Sirna, which had a number of pipeline candidates moving toward the clinic, its then-head of RNA medicines, Alan Sachs, would only state that RNAi was an early-stage modality and that “we’re all going to have to wait and see how Merck will enable itself through the use of [Sirna’s] technologies” (GSN 11/2/2006).

Since then, Merck has played up the impact Sirna has had on its drug-discovery and target-validation efforts, but made little mention of its RNAi therapeutics work, with company officials only indicating in past years that significant challenges remain for the field.

For example, in late 2008 Sachs said during a keynote address at the Drug Information Association Oligonucleotide-based Therapeutics conference that delivery was, “beyond a shadow of a doubt ... the number one problem” facing RNAi drug developers, adding that “I don’t think that we’re even close to finding a solution to this problem.”

While finding success for an RNAi drug is “still all about delivery,” the industry has made “a lot of strides” since Sachs made his comments,” Caldwell said, citing Alnylam's recently released phase I data on its systemically delivered transthyretin-mediated amyloidosis treatment ALN-TTR01 as a particularly compelling development in the field (GSN 12/1/2011).

Merck itself is primarily focused on three approaches, including lipid nanoparticles and polymer conjugates, Caldwell said. It is also exploring what it calls single chemical entities, or SCEs, which are “simple siRNAs with various modifications and peptides to increase targeting and uptake efficiency.”

The SCE approach “is really the same as the dynamic polymer conjugate technology [developed by Mirus Bio and now owned by Arrowhead research] except the [Mirus technology] uses a large polymer,” he noted.
“The single chemical entity is much smaller, and therefore may have better attributes in terms of bio-distribution and other features that are attractive from a drug-development perspective.”

At the same time, Merck evaluates “hundreds of alternative approaches” from outside parties, taking advantage of the “great work being done, not only in companies but in academia.

“I wouldn't be surprised if there is another delivery platform coming down the pike at some point in the near future,” he said.

Nevertheless, while Caldwell is sanguine about Merck's chances of clearing the delivery hurdle and having an siRNA drug ready for clinical testing in the next couple of years, “anything can happen and the science is going to dictate whether we're ready to go or not.”

Aware of the potential for immune stimulation and other adverse events, “we're not going to go into the clinic until we're feeling very good about the safety of what we're going to put into people,” he stressed. “That's primarily the reason we haven't gone in yet.”

It is for this same reason that Merck has yet to fully embrace RNAi-related technologies such as antisense or microRNA antagonists.

“We do a lot of due diligence evaluations to keep on top of those areas … just to make sure that we're competitive,” Caldwell said, adding that “we've been really encouraged” by work from Isis Pharmaceuticals in antisense and Santaris Pharma in miRNA inhibition.

But “our strategy has mainly been to benefit in those therapeutic modalities from the work of others,” he said. “We've definitely learned [from] and appreciate the things other companies have done to advance the field.”

Should one of these technologies prove to be safe and, importantly, offer a better therapeutic index than an RNAi approach, “we're open” to it, he said. “We're not stuck on siRNAs.”


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